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Disubstituted aniline compounds

a technology of aniline compounds and substituted aniline, which is applied in the field of substituted aniline compounds, can solve the problems of excess proliferation of leukemic cell lines and inability to complete differentiation, and achieve the effect of inhibiting the proliferation of such cells

Active Publication Date: 2012-02-21
MERCK SHARP & DOHME LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new group of compounds that can be used to treat cancer. These compounds can stop the growth of cancer cells and cause them to die. They can also be used to treat other diseases such as autoimmune, allergic, and inflammatory diseases, as well as neurodegenerative diseases. The invention provides pharmaceutical compositions and safe dosing regimes for these compounds.

Problems solved by technology

In this manner, the neoplastic cell is unable to complete differentiation and leads to excess proliferation of the leukemic cell line.

Method used

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  • Disubstituted aniline compounds
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  • Disubstituted aniline compounds

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0229]

Methyl 4-(dibenzylamino)benzoate

[0230]To a solution of methyl 4-iodobenzoate (1100 mg, 0.38 mmol) in dimethylacetamide (5 mL) is added N-benzyl-1′-phenylmethanamine (221 μL, 1.15 mmol) and K3PO4 (405 mg, 1.9 mmol). The reaction is degassed by freeze-pump-thaw three times. Pd[Pd(t-Bu)3]2 (39 mg, 0.076 mmol) is added and reaction is allowed to stir at 100° C. for 12 hours overnight. The crude reaction mixture was diluted with EtOAc (25 mL) and then washed with dH2O (1×10 mL). The organic layer was dried over MgSO4, filtered, concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (10-100% MeCN / H2O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and gave the desired methyl 4-(dibenzylamino)benzoate which was confirmed by MS: cal'd 332.2 (MH+), exp 332.2 (MH+).

example 2

[0231]

N-(2-aminophenyl)-4-(dibenzylamino)benzamide

[0232]To a solution of methyl 4-(dibenzylamino)benzoate (52 mg, 0.16 mmol) in a 2:1 mixture of THF / dH2O was added LiOH (10 mg, 0.48 mmol). Tetra-butyl ammonium hydroxide (2 mL, 0.1N solution in toluene / MeOH) was added to the reaction and allowed to stir at room temperature for 6 hours. The solvent was concentrated in vacuo and the reaction mixture was azeotroped with MeOH several times then placed on the high vacuum for 2 hours to dry to provide the desired 4-(dibenzylamino)benzoic acid which was confirmed by MS: cal'd 318.1 (MH+), exp 318.1 (MH+).

[0233]To a solution of 4-(dibenzylamino)benzoic acid (50 mg, 0.16 mmol) in DMF was added EDC (181 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol) and phenylenediamine (171 mg, 1.58 mmol) were which was allowed to stir at room temperature for 12 hours. The crude reaction mixture was diluted with EtOAc (20 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, ...

example 3

[0234]

Methyl 4-{[2-(dimethylamino) ethyl]amino}benzoate

[0235]Methyl 4-iodobenzoate (1 g, 3.82 mmol), XANTPHOS (0.033 g, 0.057 mmol), Pd2(dba)3 (0.035 g, 0.038 mmol), Cs2CO3 (1.741 g, 5.34 mmol) was added to a sealed tube with septa and purged with argon 3×. N,N-dimethyl-1,2-ethanediamine (0.404 g, 4.58 mmol) and 1,4-Dioxane (4 mL) was then added and was stirred at 110° C. for Overnight. The reaction mixture was cooled to room temp and diluted with ethyl acetate and filtered through celite. The organic solvent was concentrated. The product was used without further purification. MS: cal'd 223 (MH+), exp 223 (MH+).

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Abstract

The present invention relates to a novel class of disubstituted aniline compounds. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and / or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and / or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the compounds of the instant invention and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of these compounds in vivo.

Description

PRIORITY CLAIM[0001]This application is a §371 application of PCT / US07 / 009642 that was filed on Apr. 20, 2007, which claims priority from the U.S. Provisional Application No. 60 / 795,405, filed on Apr. 26, 2006, now expired.FIELD OF THE INVENTION[0002]The present invention relates to a novel class of disubstituted aniline compounds. These compounds can inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and / or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and / or treatment of diseases of the central nervous system (CNS), such as neurodegenerative disea...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/381C07C311/08C07D333/24A61K31/166C07C233/02
CPCC07C229/60C07C237/04C07C237/40C07D333/20A61P1/00A61P1/04A61P1/16A61P1/18A61P3/10A61P9/10A61P11/00A61P11/02A61P11/06A61P13/12A61P17/02A61P17/06A61P19/02A61P19/10A61P21/00A61P25/00A61P25/04A61P25/16A61P25/28A61P29/00A61P31/18A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08
Inventor HEIDEBRECHT, RICHARDMETHOT, JOEYMAMPREIAN, DAWNMILLER, THOMASSILIPHAIVANH, PHIENG
Owner MERCK SHARP & DOHME LLC
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